Iodine, including organically bound iodine, inorganic iodine and molecular iodine, i.e. I.sub.2, has been used to treat human diseases. Iodine-containing compounds have been employed extensively as expectorants. U.S. Pat. Nos. 4,187,294; 4,338,304 and 4,394,376 disclose compositions containing protein-bound iodine for the treatment of hypercholesteremia, diabetes and hyperlipemia. U.S. Pat. No. 4,259,322 discloses tuberculosis medication containing sodium iodide. Most recently, U.S. Pat. Nos. 4,816,255; 5,171,582; 5,250,304 and 5,389,385 disclose compositions of "elemental iodine" (I.sub.2) in water for oral administration in humans to treat a variety of human diseases. U.S. Pat. No. 5,589,198 discloses the benefits of using elemental iodine or "iodine metal" with pharmaceutically acceptable carriers in the treatment of fibrocystic breast syndrome.
Much of the prior art literature refers to "iodine" in an imprecise manner. The word iodine has been used in the literature to refer to several distinct chemical species that contain iodine atoms. Many different compounds with distinct and materially different properties contain iodine. For example, the literature on iodine disinfection clearly shows that the biocidal efficacy of diverse iodine species is profoundly different; molecular iodine (I.sub.2) is an active biocide while iodide (I.sup.-) has no biocidal activity. Traditional beliefs in the field of toxicology (R. C. Haynes Jr and F. Murad, "Thyroid and Antithyroid Drugs" in Goodman and Gilman's the Pharmacological Basis of Therapeutics, Eds. A. G. Gilman et al., 7.sup.th ed., pp. 682-815, 1985, W. B. Saunders, Philadelphia) have held that molecular iodine and iodide have identical toxicity profiles; however, no direct experimental data was used to support this assumption. In fact, the toxicity and therapeutic efficacy of these different species of iodine could vary dramatically just as their biocidal activity does. Unfortunately, the pharmaceutical literature on iodine has not drawn distinctions between the properties of the many different chemical species that contain iodine atoms.
The most serious concern for administration of an iodine pharmaceutical relates to the potential for toxic reactions. In this regard, it is believed that iodide is the form of iodine responsible for "iodide poisoning" or "iodism." There is no way of predicting which patient will react unfavorably to iodide, and an individual may vary in their sensitivity to iodide from time to time. A series of symptoms can result from iodism. Symptoms can include burning in the mouth and throat; soreness of the teeth and gum; increased salivation; coryza, irritation of the respiratory tract; cough; headache; enlarged glands; inflammation of the pharynx, larynx and tonsils; skin lesions; gastric irritation; diarrhea; fever; anorexia and depression; and severe and sometimes fatal eruptions (ioderma) may occur. In essence, human consumption of iodide at levels in excess of the range (0.150 to 1.0 mg/day) established by FDA researchers (J. A. Pennington, "A review of iodine toxicity reports", J. Am. Dietetic Assoc., Vol. 90, pp. 1571-1581) presents a health risk.
The only scientific studies on the relative oral toxicity of molecular iodine and iodide was performed during the early 1990s (Karla Thrall, Ph.D. Thesis, "Formation of Organic By-Products Following Consumption of Iodine Disinfected Drinking Water", Summary and Conclusion Section, Oregon State University, Department of Chemistry, 1992). The weight of a mammals thyroid is one key diagnostic measure used to evaluate the toxicity of an iodine composition. Subchronic administration of iodide to male rats increased their thyroid weight at an iodide concentration of 10 mg/kg; molecular iodine did not effect thyroid weight even at concentrations of 100 mg/kg (Sherer et al., Journal of Toxicology and Environmental Health, Vol. 32, pp. 89-101, 1991). This study by Sherer did not measure an increase in the steady state levels of thyroid hormones until animals were exposed to repeated daily doses of molecular iodine at 10 mg per kilogram of body weight. It can be concluded from these studies that iodide can effect thyroid weight in mammals at concentrations that are 10 fold less than a comparable effect from molecular iodine. Another way to state this is that it required ten time more molecular iodine than iodide to effect animal thyroid function with an orally administered iodine composition.
The human body contains approximately 18 to 20 mg of iodine. Iodine is an essential component of thyroxine and tri-iodothyronine. These hormones are essential for the maintenance of normal metabolic activity and they have an effect on almost every mammalian tissue. Excess iodine can lead to an imbalance in thyroid hormones. The reduced toxicity on the thyroid gland exhibited by molecular iodine as compared to iodide in the studies by Sherer et al. has important implications for design of an oral iodine pharmaceutical. These studies indicate that, all other factors being equal, molecular iodine is a preferred form of iodine for an oral drug. This would be especially true for disease states that require chronic administrations of said iodine pharmaceutical.
An early observation of the association of thyroid/iodine with the human female breast was made in 1896, by Dr. Beatson, who treated metastatic breast cancer using desiccated thyroid in large doses. Desiccated thyroid contains an abundance of protein-bound iodine. An early association of an iodine deficiency state and benign breast dysplasia was reported in 1966 by a clinician who reported a 71% improvement rate in women with dysplastic mastodynia treated with iodine (Vishnyakova V. V. et al., "On the Treatment of Dyshormonal Hyperplasia of Mammary Glands", Vestin. Sakad. Med. Mauk. S.S.S.R., Vol. 21:p. 19, 1966). Treatment of mammary dysplasia using traditional Chinese medicines like Sargassum, which contains a high iodide concentration, has provided cure rates of 65.4 percent. Ghent (U.S. Pat. Nos. 5,389,385 and 5,589,198) explored the use of elemental iodine treat a variety of human diseases. The scientific literature provides clear evidence that iodine in several different forms is an effective therapeutic against many different mammalian diseases.
Animal models of fibrocystic breast syndrome have been studies for over 40 years. Several studies provide evidence that indicates iodine can reverse this condition. Studies in humans have shown improvement or complete elimination of fibrocystic breast syndrome after several months of iodine therapy. Other mammalian disease states that have been treated with iodine include ovarian cysts, premenstrual syndrome, breast cancer and endometriosis.
For convenience, certain terms employed in the specification, examples, and appended claims are defined below.
The term "molecular iodine" as used herein, refers to diatomic iodine, which is represented by the chemical symbol I.sub.2, which exists in a liquid.
The term "elemental iodine" as used herein, refers to solid diatomic iodine, which is represented by the chemical symbol I.sub.2.
The term "iodide" or "iodide anion" refers to the species which is represented by the chemical symbol I.sup.31. Suitable counter-ions for the iodide anion include sodium, potassium, calcium, and the like.
The term "triiodide" refers to the species which is represented by the chemical symbol I.sub.3.sup.-. It is recognized by one skilled in the art that triiodide is formed from the interaction of one iodide anion and one molecule of molecular iodine under the laws of mass action and that triiodide rapidly dissociates into one iodide anion and one molecule of molecular iodine.
The term "total iodine" as used herein, refers to the following iodine species: molecular iodine, iodide, organically complexed forms of iodine, covalently bound forms of iodine, iodite, triiodide, polyiodides containing more than 5 atoms of iodine and elemental iodine.
The term "rate of iodine generation" as used herein, refers to the rate at which molecular iodine is formed in a liquid environment.
The term "ratio of molecular iodine" as used herein, refers to the ratio of molecular iodine (I.sub.2) to all other iodine species such as iodide, triiodide and polyiodides containing more than 5 atoms of iodine or total iodine.
Elemental iodine is sold commercially as blue-black crystals with a high metallic luster. The major difficulty with the preparation of a suitable oral composition of molecular iodine is related to the basic physical chemistry of this element. All solid forms of elemental iodine sublime readily to generate a violet-colored vapor. In fact, atmospheric iodine is a major component of global iodine cycling. Unfortunately, the facile sublimation of elemental iodine introduces an inherent instability which precludes its use, per se, as the active ingredients in a pharmaceutical preparation. Other chemicals are combined in some form with elemental iodine in order to provide stable preparations that contain molecular iodine. There are three different types or categories of oral iodine compositions that have been used to treat disease states in mammals: (1) organically bound iodine including both covalent binding and hydrophobic/ionic complexes, (2) inorganic iodine and (3) aqueous molecular iodine.
Organic iodine compounds, which have been used "off-label" as nutritional iodine supplements, are designed for use in the area of radiographic contrast mediums (radiopaque compounds). For instance, lymphography is used to detect and evaluate abnormalities of the lymphatic system and as a guide to surgical dissection of lymph nodes. Iodine-based radiopaque compounds are likewise employed in several different diagnostic procedures, i.e. cholecystography, myelography, urography, angiographycholangiography. A number of different organic iodine compounds have been used for this purpose including .beta.-(4-hydroxy-3,5-diiodophenyl)-.alpha.-phenylpropionic acid, .beta.-(3-amino-2,4,6-triiodophenyl)-.alpha.-ethylpropionic acid, iodophenylundecylate, 3,5-diacetamido-2,4,6-triiodo-benzoate, 3,5-diacetamido-2,4,6-triiodo-benzoic acid, and ethiodized oil. The iodine atoms in these compounds are covalently bound to organic molecules. Other forms of organic iodine have been used as therapeutics including protein-bound iodine, desiccated thyroid and iodine metabolically incorporated into chicken eggs.
Inorganic iodine compositions that have been used as oral therapeutics include sodium or potassium iodide; tincture of iodine or Lugol's solution; and organic iodides that yield iodide. Aqueous compositions of these species inherently contain a very low and/or unpredictable ratio of molecular iodine to total iodine. In fact, these compositions usually contain less molecular iodine on a molar basis than other forms of iodine. For instance, Lugol's solution contains approximately 129,000 ppm of total iodine but only 170 ppm of molecular iodine or a ratio of 0.0013.
Pure aqueous solutions of molecular iodine do not exist in commerce. Molecular iodine is known to be unstable in water and this instability is a function of pH. Molecular iodine is hydrated by water and, in an aqueous system, undergoes the series of reactions shown below in equations 1 to 3. EQU I.sub.2 +H.sub.2 O=HOI+I.sup.- +H.sup.+ ( 1) EQU 3HOI=IO.sub.3.sup.- +2I.sup.- +3H.sup.+ ( 2) EQU I.sub.2 +I.sup.- =I.sub.3.sup.- ( 3)
It is not possible to make and bottle a stable aqueous solution that contains at least a molecular iodine ratio of 0.65. For clinical applications, this limitation has previously been addressed by preparing aqueous solutions of iodine immediately prior to use and then consuming them. Elemental iodine dissolves very slowly in water. The long time necessary to dissolve elemental iodine causes the loss of some nascently formed molecular iodine due to its reaction with water as shown in equation 1 above. As a result, there are problems of consistency and ease of use with this method. Compositions that contain several different pharmacologically active agents with diverse toxicity profiles are not preferred as pharmaceutical agents.
An ideal drug produces its desired effect in all patients without causing toxic effects. The relationship between the desired and undesired effects of a drug is termed its therapeutic index or selectivity. The therapeutic index for a drug is frequently represented as the ratio of the median toxic dose to the median effective dose. In clinical studies, drug selectivity is often expressed indirectly by summarizing the pattern and nature of adverse effects produced by therapeutic doses of the drug and by indicating the proportion of patients with adverse side effects. Each separate iodine species should be considered to be a unique drug entity since they have been shown to have different oral toxicity and therapeutic index profiles. Therefore, a preferred "iodine" therapeutic is a composition wherein the all or an overwhelming majority of the total iodine atoms present are in the desired form.
The prior art demonstrates that molecular iodine is an effective therapeutic agent in a number of disease states. For instance, Eskin et al. (Biological Trace Element Research, Vol. 49, pp. 9-18, 1995) demonstrated that molecular iodine is "distinctly more effective in diminishing ductal hyperplasia and perilobular fibrosis in the mammary glands than iodide". The scientific literature also indicates that the oral toxicity of iodide is greater than that for molecular iodine. Another way to state this is to say that the prior art in animals and humans demonstrates that the most therapeutic form of iodine, when administered orally, is molecular iodine; also, the least toxic form of iodine when administered orally is molecular iodine. Therefore, the prior art indicates that all of the iodine in a preferred oral iodine pharmaceutical should be molecular iodine. This distinction in toxicity is especially important for a treatment regime that requires chronic dosing. As a practical matter it is acceptable to limit the potential for toxicity due to iodide to a safe range. In order to accomplish this latter objective it is necessary to limit the concentration of iodide by weight to no more than 1,000 ug/day of iodide when administered chronically and preferably it should provide no more than 150 ug/day and most preferably it should provide no more than 50 ug/day.
Since the toxicity of an oral pharmaceutical iodine drug is directly related to the ratio and concentration of the different iodine species present; the known instability of the I.sub.2 species presents a challenge to the development of an oral iodine pharmaceutical composition with a preferred therapeutic index. This application describes methods to overcome the problems that exist with the prior art in the delivery of molecular iodine in an acceptable stable oral pharmaceutical.